The proposed research seeks to accomplish two goals: first, to investigate the structure-activity requirements of a potent angiotensin-converting enzyme with oral and intravenous activity in vivo. Chemical modification of the ketone group, the amide groups, and the side chain groups, will be made in an effort to learn more about the effect that structural changes in 5 will have on its angiotensin-converting enzyme activity. Each compound will first be tested for ability to inhibit angiotensin converting enzyme in vitro. Inhibitors that inhibit the enzyme with the same range of activity or better activity than the parent compound 5 will be tested in vivo. In vivo tests in the rat will (1) investigate the ability of the new inhibitors when given by intravenous or oral routes to inhibit an angiotensin I induced blood pressure rise, and (2) determine the ability of the new inhibitors to lower blood pressure in spontaneously hypertensive rats and in rats made hypertensive surgically. Chemical changes in 5 that yield more potent converting enzyme inhibitors will be included in a second stage of inhibitors with more than one chemical change in 5. We will also synthesize an analog of a known peptide inhibitor of renin, Leu-Leu-Val-Phe-OEt, in which the Leu-Leu amide linkage is replaced by a ketomethylene group. The new compound will be tested in vitro as an inhibitor of renin. If good renin inhibition is seen with this new compound, we will begin a study of its structure-renin inhibition activity requirements similar to that proposed for the angiotensin converting enzyme inhibitor 5.